CLINICAL PHARMACOLOGY
Morphine is a natural product that is the prototype for the class of natural and synthetic opioid analgesics. Opioids produce a wide spectrum of pharmacologic effects including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release and physical dependence.
Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a pure agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.
EFFECTS ON THE CENTRAL NERVOUS SYSTEM
The principal therapeutic actions of morphine are analgesia, sedation and alterations of mood. Opioids of this class do not usually eliminate pain, but they do reduce the perception of pain by the central nervous system.
Morphine produces respiratory depression by reducing the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension (or to direct electrical stimulation).
Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.
Morphine causes miosis, even in total darkness, and little tolerance develops to this effect. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g. pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.
EFFECTS ON THE GASTROINTESTINAL TRACT
Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.
EFFECTS ON THE CARDIOVASCULAR SYSTEM
Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by morphine and can contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.
PHARMACODYNAMICS
The relationship between the blood level of morphine and the analgesic response will depend on the patient's age, state of health, medical condition, and the extent of previous opioid treatment.
A minimum effective concentration (MEC) of morphine for pain relief has been reported as 27.2 ± 14.5 ng/mL (mean ± SD) in cancer patients treated with morphine solution. These results compare with the MEC for plasma morphine reported as 14.7 ± 4.8 ng/mL (mean ± SD) in patients with postoperative pain. The high degree of variation is of clinical significance as it may result in either under-dosing or over-dosing if the dosage is not adjusted to the patient's clinical status and analgesic response (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
For opioid-tolerant patients the situation is much more complex. Some patients will become rapidly tolerant to the analgesic effects of morphine, and will require high daily oral morphine doses for adequate pain control. Since the development of tolerance to both the therapeutic and adverse effects of opioids is highly individualized, the dose of morphine should be individualized to the patient's condition and should not be based on an arbitrary choice of a dose or blood level to be achieved.
PHARMACOKINETICS
KADIAN® capsules contain polymer coated sustained release pellets of morphine sulfate that release morphine significantly more slowly than from morphine sulfate tablets and shorter-acting controlled-release oral morphine sulfate preparations. KADIAN® activity is primarily due to morphine. One metabolite, morphine-6-glucuronide, has been shown to have analgesic activity, but poorly crosses the blood-brain barrier.
Following oral administration, the extent of absorption is essentially the same for immediate or sustained release formulations, although the time to peak blood level (Tmax) will be longer and the Cmax will be lower for formulations that delay the release of morphine in the gastrointestinal tract.
Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites (55 to 65%) which are then renally excreted. The terminal half-life of morphine is 2 to 4 hours, however, a longer term half-life of about 15 hours has been reported in studies where blood has been sampled up to 48 hours.
The single-dose pharmacokinetics of KADIAN® are linear over the dosage range of 30 to 100 mg. The single dose and multiple dose pharmacokinetic parameters of KADIAN® in normal volunteers are summarized in Table 1.
Table 1:Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple dose study in patients with cancer pain.
| Regimen/ Dosage Form |
AUC #,
+ (ng.h/mL) |
Cmax+ (ng/mL) |
Tmax (h) |
Cmin+ (ng/mL) |
Fluctuation * |
|
Single Dose (n=24)
|
|
KADIAN® Capsule
|
271.0 (19.4) |
15.6 (24.4) |
8.6 (41.1) |
na ^ |
na
|
|
Controlled-Release Tablet
|
304.3 (19.1) |
30.5 (32.1) |
2.5 (52.6) |
na
|
na
|
|
Morphine Solution
|
362.4 (42.6) |
64.4 (38.2) |
0.9 (55.8) |
na
|
na
|
|
Multiple Dose (n=24)
|
|
KADIAN® Capsule q24h
|
500.9 (38.6) |
37.3 (37.7) |
10.3 (32.2) |
9.9 (52.3) |
3.0 (45.5) |
|
Controlled-Release Tablet q12h
|
457.3 (40.2) |
36.9 (42.0) |
4.4 (53.0) |
7.6 (60.3) |
4.1 (51.5) |
|
# For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady state
|
|
+ For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
|
|
* Steady-state fluctuation in plasma concentrations = Cmax-Cmin/Cmin |
| ^Not applicable
|
|
ABSORPTION
Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes. However, following the administration of an equal amount of KADIAN® to healthy volunteers, this occurs, on average, after 8 hours. As with most forms of oral morphine, because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.
Food Effects: While concurrent administration of food slows the rate of absorption of KADIAN®, the extent of absorption is not affected and KADIAN® can be administered without regard to meals. Steady State: When KADIAN® is given on a fixed dosing regimen to patients with chronic pain due to malignancy, steady state is achieved in about two days. At steady state, KADIAN® will have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution and some other controlled-release preparations (see Graph 1).
When given once-daily (every 24 hours) to 24 patients with malignancy, KADIAN® had a similar Cmax and higher Cmin at steady state in clinical usage, when compared to twice-daily (every 12 hours) controlled-release morphine tablets (MS Contin®), given at an equivalent total daily dosage (see Graph 2 and Table 1). Drug-disease interactions are frequently seen in the older and more gravely ill patients, and may result in both altered absorption and reduced clearance as compared to normal volunteers (see Geriatric, Hepatic Failure, and Renal Insufficiency sections).
DISTRIBUTION
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain.
The volume of distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to plasma proteins.
Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier.
Morphine also crosses the placental membranes (see PRECAUTIONS - Pregnancy) and has been found in breast milk (see PRECAUTIONS - Nursing Mothers).
METABOLISM
The major pathway of the detoxification of morphine is conjugation, either with D-glucuronic acid in the liver to produce glucuronides or with sulfuric acid to give morphine-3-etheral sulfate. Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%). Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses and at steady state for KADIAN®, 12-hour controlled-release morphine sulfate tablets and morphine sulfate solution.
M3G has no significant analgesic activity. M6G has been shown to have opioid agonist and analgesic activity in humans. Excretion
Approximately 10% of morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the feces.
The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2.0 hours. Longer plasma sampling in some studies suggests a longer terminal half-life of morphine of about 15 hours.
SPECIAL POPULATIONS
Geriatric: The elderly may have increased sensitivity to morphine and may achieve higher and more variable serum levels than younger patients. In adults, the duration of analgesia increases progressively with age, though the degree of analgesia remains unchanged. KADIAN® pharmacokinetics have not been investigated in elderly patients (>65 years) although such patients were included in the clinical studies. Nursing Mothers: Morphine is excreted in the maternal milk, and the milk to plasma morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant depends on the maternal plasma concentration, amount of milk ingested by the infant, and the extent of first pass metabolism.
Pediatric: Infants under 1 month of age have a prolonged elimination half-life and decreased clearance relative to older infants and pediatric patients. The clearance of morphine and its elimination half-life begin to approach adult values by the second month of life. Pediatric patients old enough to take capsules should have pharmacokinetic parameters similar to adults, dosed on a per kilogram basis (see PRECAUTIONS - Pediatric Use).
Gender: No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies. Race: Pharmacokinetic differences due to race may exist. Chinese subjects given intravenous morphine in one study had a higher clearance when compared to caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min). Hepatic Failure: The pharmacokinetics of morphine were found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity.
Renal Insufficiency: The pharmacokinetics of morphine are altered in renal failure patients. AUC is increased and clearance is decreased. The metabolites, M3G and M6G accumulate several fold in renal failure patients compared with healthy subjects. Drug-Drug Interactions: The known drug interactions involving morphine are pharmacodynamic, not pharmacokinetic (see PRECAUTIONS - Drug Interactions).
CLINICAL STUDIES
A total of 177 healthy subjects and 337 patients with cancer pain participated in a total of 15 studies (10 pharmacokinetic and 6 clinical; one study reported both pharmacokinetic and clinical data). Of these individuals, 158 healthy subjects and 268 patients received KADIAN®. In the controlled clinical studies patients were followed for a median duration of 7 days and in the open label studies patients were followed for up to 12-24 months. KADIAN® was compared to oral morphine solution and to either MS Contin® or to a 12-hour controlled-release morphine tablet bioequivalent to MS Contin® using trial designs that followed the clinical and pharmacokinetic performance of each treatment in cancer patients receiving chronic opioid therapy.
In two controlled studies, patients with moderate to severe cancer pain were titrated with immediate-release morphine (IRM) solution or tablets to a stable total daily dose of morphine for at least three consecutive days, then randomized to KADIAN® or 12-hour controlled-release morphine for seven days of observation. KADIAN® given once a day proved similar to the same total dose of morphine given in divided doses in a 12-hour dosage form, with respect to pain relief, use of rescue medication, patient and investigator global assessment, and quality of sleep. Individual patient differences in the pattern of pain control emphasize the need to individualize both dose and dosing interval (see DOSAGE AND ADMINISTRATION).
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